Design and Synthesis of Novel <i>N</i>-Benzylidene Derivatives of 3-Amino-4-imino-3,5-dihydro-4<i>H</i>-chromeno[2,3-<i>d</i>]pyrimidine under Microwave, <i>In Silico</i> ADME Predictions, <i>In Vitro</i> Antitumoral Activities and <i>In Vivo</i> Toxicity

Abstract

The synthesis of a series of new N-benzylidene derivatives of 3-amino-4-imino-3,5-dihydro-4H-chromeno[2,3-d]pyrimidine 10(a-l) bearing two points of molecular diversity is reported. These new compounds were synthesized in five steps including two steps under microwave dielectric heating. They were fully characterized using 1H and 13C NMR, FTIR and HRMS. The in silico physicochemical properties of compounds 10(a-l) were determined according to Lipinski’s rules of five (RO5) associated with the prediction of their bioavailability. These new compounds 10(a-l) were tested for their antiproliferative activities in fibroblasts and eight representative human tumoral cell lines (Huh7 D12, Caco2, MDA-MB231, MDA-MB468, HCT116, PC3, MCF7 and PANC1). Among them, the compounds 10h and 10i showed sub-micromolar cytotoxic activity on tumor cell lines (0.23 50 50 > 25 μM). A dose-dependent inhibition of Store-Operated Ca+2 Entry (SOCE) was observed in the HEK293 cell line with 10h. In vitro embryotoxicity and angiogenesis on the mCherry transgenic zebrafish line showed that 10h presented no toxic effect and no angiogenic effect on embryos with a dose of 5 μM at 72 hpf.

Keywords

• 2-amino-4<i>H</i>-chromene
• 4<i>H</i>-chromeno[2,3-<i>d</i>]pyrimidine
• microwave irradiation
• tumoral cell line
• cytotoxicity
• Lipinski’s rules of five